The connective tissue of vertebrates includes bone and cartilage as well as tissue that underlies the skin, envelops muscle, and occupies space between internal organs. The primary building blocks of connective tissue are proteoglycans (PG), which are linked to collagen fibers to form connective tissue. Proteoglycan subunits are comprised of glycoaminoglycans (also known as GAGs or mucopolysaccharides) attached in large numbers to a core protein, with these proteoglycan subunits being attached to a very long hyaluronic acid molecule via protein links to form aggregating proteoglycan. GAGs are long-chain polymers with monomer units comprising an aminosugar and an organic acid or sugar. One type of GAG is chondroitin sulfate, which is composed of glucuronic acid and N-acetyl galactosamine sulfate. Glucosamine is a key precursor to both GAGs and hyaluronic acid molecules, which are the primary components of PGs, as discussed above. In fact, the bioavailability of glucosamine is the rate-limiting step in the synthesis of GAGs and PGs.
Connective tissue serves to maintain the structure of the body parts in relation to one another and to cushion the interfaces between bones, among many other purposes. Normal, healthy connective tissue is resilient, compressive, and possessive of a "slippery" type surface, while diseased or damaged connective tissue is rough and brittle. Damage to connective tissue serving to cushion bone interfaces and ease skeletal movement (such as at the knee joint) may actually result in the bones grinding against one another during movement, causing considerable pain and even constraint of movement. Damage to, or disease of, the various types of connective tissues can lead to a variety of adverse effects for humans and pets.
The breakdown of connective tissue in the vertebrate body is a natural occurrence--connective tissue is continuously restored and maintained in a healthy break-down/restoration cycle. In fact, it is reported that GAGs and PGS are continuously restored in connective tissues with an approximately 700 d half life in healthy human joints (L. Bucci, Nutrition Applied to Injury Rehabilitation and Sports Medicine, CRC Press, Inc. (1995), p. 177). However, the natural breakdown of connective tissue may be accelerated beyond the rate of restoration due to a wide variety of causes, including disease processes and trauma. Examples of such disease processes include diseases afflicting the joints, such as osteoarthritis, chronic degenerative joint diseases, and autoimmune inflammatory joint diseases; diseases afflicting the bone, such as osteoporosis; and diseases afflicting the skin, such as ulcers. Examples of types of trauma that may accelerate the breakdown of connective tissue include bone fracture, skin burns, and other traumatic injuries.
The bioavailability of glucosamine and GAGs, such as chondroitin sulfate, is believed to bolster the restoration of connective tissue in a variety of ways. For example, glucosamine stimulates the incorporation of other precursors, such as GAGs, PGs, and collagen, into the connective tissue matrix and serves as a precursor to GAG synthesis. Chondroitin sulfate serves to inhibit degradative enzymes and stimulates GAG and PG synthesis in connective tissue cells, particularly chondrocytes (see Bucci, p. 184). The vertebrate body synthesizes GAGs, such as in chondrocytes (cartilage), fibroblasts (skin, ligaments), and osteoblasts (bone).
In addition to self-synthesis of PG and PG precursors, humans and pets ingest a relatively small amount of PGs, GAGs, and glucosamine as part of a normal balanced diet. It is estimated that an average human daily intake of GAGs may approach 1 gram (Id. at 180). It is reported that animals that regularly consume meat have an enhanced ability to digest GAGs compared to those animals that primarily consume vegetation, such as rabbits (Id. at 181). It is also reported that the bioavailability of orally-ingested glucosamines is excellent (Id. at 196).
Extracts of the individual precursors to PGs, such as glucosamine and GAGs like chondroitin sulfates, are available as dietary supplements to increase their bioavailability over that achieved from both self-synthesis and normal dietary ingestion. Glucosamine is available as dietary supplements in the form of glucosamine salts, including glucosamine sulfate, glucosamine.HC1, glucosamine iodide, glucosamine sulfate, and N-acetylglucosamine. Examples of commercially-available glycosaminoglycan supplements include Rumalon.RTM. and Arteparon.RTM., which are pharmaceutical preparations available from Robapharm in Basel, Switzerland and Luitpold-Wek in Junich, Germany, respectively. Rumalon is a glycosaminoglycan-peptide complex extracted from bovine bone marrow and cartilage. Arteparon is a glycosaminoglycan polysulfate that is a semisynthetic mixture of GAGs originally prepared from bovine lungs and trachea. Both Rumalon.RTM. and Arteparon.RTM. are supplied in vials for injections and are not presently administered orally.
Certain dietary supplement compositions are known that offer combinations of PG precursors in extract form. For example, U.S. Pat. No. 5,364,845, issued to Henderson and assigned on its face to Nutramax Laboratories, Inc., discloses a therapeutic composition that includes glucosamine, chondroitin sulfate, and manganese ascorbate in capsule form. U.S. Pat. Nos. 5,503,990 and 5,654,166, issued to Kurth, disclose the preparation of powdered hormone-free bovine cartilage for pharmaceutical cancer treatment and food supplement products, representing another use for connective tissue ingestion aside from connective tissue restoration. According to Bucci, glucosamine salts have shown efficacy of treatment at daily supplemental doses of 1500 mg, divided into two or three doses (see Bucci, p. 202), while daily doses of chondroitin sulfates should be at least 1 gram (Id. at 184). Neither chondroitin sulfates nor glucosamine are believed to be toxic at even much higher levels.
Although the oral ingestion of dietary supplements containing such PG precursors as chondroitin sulfates and glucosamine is known to effectively treat connective tissue disorders, among other maladies, the oral administration of dietary supplements may not be easily accomplished. For example, it can be difficult to orally administer dietary supplements to pets. Moreover, many humans have difficulty in swallowing capsules, or simply dislike taking pills or capsules.
Additionally, dietary supplements can be relatively expensive and complex to manufacture. Presently, dietary supplements containing the building blocks of connective tissue are produced by an extraction process. An example of such an extraction process is disclosed by Kurth (U.S. Pat. No. 5,654,166), wherein bovine tracheal cartilage is subjected to the following steps to achieve extraction: (1) raw bovine tracheal cartilage is first washed, trimmed and cut into small chunks measured in millimeters; (2) the chunks of cartilage are subjected to enzymatic digestion to digest unwanted protein; (3) the lipid fat is removed from the treated cartilage via solvent treatment; and (4) the treated cartilage is reduced to dosage form by pulverization or ball milling. Thus, the extraction process requires several rounds of chemical treatment in addition to size reduction steps to produce a dietary supplement.
In view of the above-described art, a need remains for a manner of oral administration in which therapeutic amounts of chondroitin sulfates, glucosamine, and other useful building blocks of connective tissue, are made available as components of food that will be consumed by humans or pets for daily sustenance, rather than as a dietary supplement. The manner of achieving incorporation of connective tissue precursors into primary dietary foods must necessarily be inexpensive, certainly less so than extraction processes, else the resulting foodstuff would be uneconomical.